Identification of Positive Allosteric Modulators of Acetylcholinesterase for Treatment against Organophosphorus Poisoning
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Date
2021-05
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The Ohio State University
Abstract
Acetylcholinesterase (AChE) is an enzyme that catalyzes the conversion of the neurotransmitter acetylcholine (ACh) into acetate and choline. ACh binds to muscarinic and nicotinic acetylcholine receptors triggering muscle contraction or neuronal communication. Organophosphorus (OP) nerve agents and pesticides inhibit and/or age the active site of AChE. AChE inhibition is the process by which the OP compound forms a covalent bond with the active site serine, whereas aging is the dealkylation of the OP moiety in the OP-AChE complex after inhibition. After inhibition and/or aging of AChE, a buildup of ACh in the synaptic clefts and neuromuscular junctions occurs, an event known as a cholinergic crisis, which causes severe harm and even death to an untreated individual. Currently approved therapeutics reactivate inhibited AChE, but they do not resurrect, or return to normal function, the aged form of the enzyme. Additionally, these positively charged therapeutics are incapable of crossing the blood-brain barrier, which is impermeable to charged molecules. Therefore, novel therapeutics must be developed to improve the treatment of OP poisoning. One approach to reducing the severity of OP poisoning is through the use of positive allosteric modulators of AChE. In general, a positive allosteric modulator (PAM) binds to an enzyme at a location removed from the active site and modifies the enzyme in a manner that increases its catalytic rate. Utilizing PAMs of AChE would enable remaining native AChE to increase the rate of conversion from ACh to acetate and choline, reducing the amount of AChE required to prevent cholinergic crisis. The modification of AChE caused by PAMs might also prevent OP agents from reacting with the active site serine or slow the rate of reaction. Further, the modifications caused by PAMs could potentially enhance the reactivation and/or resurrection of inhibited or aged AChE. Therefore, the initial goal of this project was to 1) identify novel PAMs of AChE, 2) test the identified compounds for prophylactic capabilities, and 3) identify which PAMs enhance the rate of reactivation and/or resurrection of AChE. However, a number of obstacles were encountered that question the results of previous work.